The need to consider the impact of previous stressors on current stress parameter measurements

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Matching the study design to the research question

Dr Schubert raises several interesting questions in his comments on our study (Lucas et al. 2007; Schubert 2008), particularly in relation to study design. He highlights the complexities of studying biological effects of a highly dynamic exposure, where the biological response may be conditional on previous experiences and exposures.

Different study designs will have different strengths and weaknesses with regard to evaluation of these issues. Our study (Lucas et al. 2007) used a cross-sectional design to examine the association between perceived stress and two measures of immune function in a large population-based sample of healthy middle-aged men and women. “Healthy” in this study meant the absence of overt physical disease. No assumptions were made about the underlying stress status of participants – within this population representative of the socioeconomic spectrum it would seem likely that the full range of underlying allostatic load status could be present. Indeed, although Schubert (2008) notes that if underlying allostatic load variation was the reason for the finding of a bi-directional effect on immune function one would expect both IgA and neopterin to be affected similarly, we did demonstrate a (non-significant) bi-directional effect on neopterin.

Schubert's studies on stress in an individual with SLE using a longitudinal design with intense exposure and outcome assessment (Schubert et al. 1999, 2003) have provided considerable data on the dynamic association between stress and various biological measures. While this setting provides data to examine questions relating to individual diurnal rhythms in stress parameters and associations between stressor exposure and biological measures, the results are not generalizable at the population level (diseased or healthy) due to the very small sample size (n = 1 in each study).

A strength of our study is that it is a large population-based sample, representative of the underlying population from which it is drawn. In addition, our study sample consists of healthy middle-aged people (a somewhat neglected research group), rather than those affected by an autoimmune disease, which itself may influence the association between stress and the immune response.

It is important to match the study design to the research question. Both the longitudinal intense study of few individuals and the population-based study of a larger, representative, sample contribute useful information. Notably, neither of these study designs is ideal for looking at long-term previous stressors. This would require a large population-based longitudinal study beginning during the in utero period to take account of maternal stress and its effects on the stress/immune axis of the developing fetus.

We recognise and acknowledged the limitations of our study design (Lucas et al. 2007). In this study setting controlled timing of specimen collection was not feasible and we used statistical methods to adjust for the time of specimen collection. The study questionnaire did not aim to measure the stress immediately before sample collection, but aimed to provide a global assessment of perceived stress in the time proximal to the biological measurement. The measurement of the effect of immediately antecedent stress is perhaps better suited to laboratory stress challenges.

Schubert (2008) suggests that study validity requires a “careful analysis of an individual's psychosocial reality together with sophisticated time series analysis.” We agree that a carefully designed large population-based prospective study, considering not only the psychosocial reality, but a wide range of other factors (some of which we did examine), including lifestyle factors such as smoking, drug and alcohol intake and physical activity, with frequent measurement of both stressor exposure and perception and a range of biological parameters would provide valuable data on the association between stress perception and immune function. One realistic alternative is to use a variety of study designs and statistical tools appropriate to the (narrowly defined) research question, and integrate the ensuing research findings.

R. M. Lucas

National Centre for Epidemiology and Population Health, ANU College of Medicine and Health Sciences, The Australian National University, Canberra, ACT, 0200, Australia, 61 02 6125 3448, 61 02 6125 5614, [email protected]

A.-L. Ponsonby

Murdoch Childrens Research Institute, Melbourne, Victoria, 3052, Australia